Insulin sensitivity, metabolic clearance rate of insulin (MCRI), and insulin secretion are traits that all have a significant impact on the risk of type 2 diabetes (T2DM). The over-arching goal of this proposal is to identify the genetic variants underlying variation in insulin resistance, MCRI, and insulin secretion in Hispanic Americans, the largest US minority group and one at high risk of T2DM. In the IRAS Family Study (funded for two five-year cycles by NHLBI), we have recruited a large Hispanic cohort and obtained detailed and novel phenotypic measures of glucose homeostasis, obesity and other traits. We have identified a substantial genetic contribution and potential genomic locations to many of these measures through heritability analysis, linkage analysis, candidate gene association studies and, most recently, a pilot genome-wide association scan (GWAS). In this renewal application, we propose to extend these findings by developing a consortium of studies that have similar measures of these critically important phenotypes related to T2DM risk and access to DNA samples in Hispanic cohorts. The GUARDIAN Consortium (Genetics Underlying Diabetes in Hispanics) has the following goals: (1) to perform a GWAS to detect loci underlying variation in glucose homeostasis traits in a multi-cohort pedigree-based set of 4685 Hispanics; (2) to translate/extend these findings to the relevant clinical disease, T2DM, by testing for association in a set of ~3500 T2DM cases and ~5500 controls; and (3) to sequence up to 12 genetic loci from our GWAS in order to identify specific variants contributing to variation in glucose homeostasis traits and susceptibility to T2DM. The unique strengths of the proposed study include the highly detailed phenotypes of glucose homeostasis in the discovery sample that have not been previously examined in the GWAS setting, the large population size available with these measures in a Hispanic cohort, and our long-standing, highly productive collaborative team. This project has great public health significance as it is focused on increasing our understanding and mechanisms for the prevention of T2DM using pre-diabetic measures of glucose homeostasis.